Thiazole Compound (as PPAR delta) Ligand and Pharmaceutical, Cosmetic and Health Food Comprised Thereof

ABSTRACT

The present invention relates to a thiazole compound as a peroxisome proliferator activated receptor δ (PPARδ) activator or pharmaceutically acceptable salts thereof, and a pharmaceutical composition, a functional cosmetic composition, a health food, health beverages, a food additive and animal feeds containing the same.

TECHNICAL FIELD

The present invention relates to the thiazole compound represented byformula 1 as a PPARδ (Peroxisome Proliferator Activated Receptor δ)ligand which can be used for the treatment of obesity, hyperlipidemia,arteriosclerosis, diabetes, dementia, Alzheimer's and Parkinson'sdisease, and used for strengthening muscles or improving memory and apharmaceutical composition, a cosmetic composition, a health food,health beverages, a food additive and animal feeds containing the same.

BACKGROUND ART

Among nuclear receptors, PPAR (Peroxisome Proliferator ActivatedReceptor) is known to have three subtypes, which are PPARα, PPARγ andPPARδ (Nature, 1990, 347, p 645-650, Proc. Natl. Acad. Sci. USA 1994,91, p 7335-7359). PPARα, PPARγ and PPARδ have tissue-specific functionsin vivo and different regions for expression. PPARα is mainly expressedin the heart, kidney, skeletal muscle and large intestines in humans(Mol. Pharmacol. 1998, 53, p 14-22, Toxicol. Lett. 1999, 110, p 119-127,J. Biol. Chem. 1998, 273, p 16710-16714), and is involved in β-oxidationof peroxisome and mitochondria (Biol. Cell. 1993, 77, p 67-76, J. Biol.Chem. 1997, 272, p 27307-27312). PPARγ is expressed in the skeletalmuscle at a low level, but mainly expressed in the adipose tissue toinduce the adipocyte differentiation and to store energy as a form offat, and is involved in homeostatic regulation of insulin and glucose(Moll. Cell. 1999, 4, p 585-594, p 597-609, p 611-617). PPARδ ispreserved evolutionarily in mammals including humans and vertebratesincluding rodents and sea squirts. The previous studies confirmed thatPPARδ plays an important role in the reproductive cell expression (GenesDev. 1999, 13, p 1561-1574) and has physiological functions ofdifferentiating neuronal cells (J. Chem. Neuroanat 2000, 19, p 225-232)in central nervous system (CNS) and wound healing with anti-inflammatoryeffect (Genes Dev. 2001, 15, p 3263-3277, Proc. Natl. Acad. Sci. USA2003, 100, p 6295-6296). Recent studies also confirmed that PPARδ isinvolved in the adipocyte differentiation and lipid metabolism (Proc.Natl. Acad. Sci. USA 2002, 99, p 303-308, Mol. Cell. Biol. 2000, 20, p5119-5128). For example, PPARδ activates the expression of key geneinvolved in β-oxidation in fatty acid catabolism and uncoupling proteins(UCPs), the gene involved in energy metabolism, which brings the effectof improving obesity (Nature 2000, 406, p 415-418, Cell 2003, 113, p159-170). The activation of PPARδ increases the HDL (High DensityLipoprotein) level, improves type 2 diabetes without weight changes(Proc. Natl. Acad. Sci. USA 2001, 98, p 5306-5311, 2003, 100, p15924-15929, 2006, 103, p 3444-3449), and favors the treatment ofarteriosclerosis by inhibiting the gene associated with arteriosclerosis(Science, 2003, 302, p 453-457). Therefore, PPARδ ligand can bedeveloped as a drug for the treatment of metabolic diseases such asobesity, diabetes, hyperlipidemia and arteriosclerosis.

PPARδ regulates mitochondria biosynthesis. When PPARδ was artificiallyover-expressed in the mouse muscles, mitochondria biosynthesis wasincreased and Type I muscle fiber was increased significantly, inaddition to the increase of fatty acid β oxidase. Therefore, constantrunning time and distance were respectively 67% and 92% increased,compared with wild type mouse (PLoS Biology, 2004, 2:e294). The increaseof mitochondria biosynthesis has a positive effect on the enhancement ofbrain functions. If mitochondria in brain cell is destroyed by oxidativestress, memory decreases significantly (Proc. Natl. Acad. Sci. USA 2002,99, p 2356-2361). Dementia, Alzheimer's and Parkinson's disease are therepresentative degenerative diseases, which demonstrate significantdecrease of learning and memory. Therefore, the mitochondriaproliferating agent developed in the present invention not onlycontributes to the improvement of memory, but also can be developed as atherapeutic agent for Alzheimer's and and Parkinson's disease.

Synthetic PPARδ ligands developed, so far, have less selectivity,compared with other PPARα and PPARγ ligands. The early selective ligandwas L-631033, developed by Merk (J. Steroid Biochem. Mol. Biol. 1997,63, p 1-8), which was produced by introducing a functional group beingable to fix side chain based on its natural fatty acid morphology. Thesame research team reported later more effective ligand L-165041 (J.Med. Chem. 1996, 39, p 2629-2654), in which the compound known as aleukotriene agonist is functioning to activate human PPARδ. Thiscompound exhibited great selectivity to hPPARδ, which is 10 times theselectivity to PPARα or PPARγ. And EC₅₀ of the compound was 530 nM.Other ligands L-796449 and L-783483 have improved affinity (EC₅₀=7.9nM), but barely have selectivity to other hPPAR subtypes.

Glaxo-Smith-Kline reported GW2433 (Chem. Biol. 1997, 4, p 909-918), thePPARα activator, which is Y-type ligand having a similar structure tothe crystal structure of the PPARδ ligand pocket. Unlike theconventional ligands known so far, this ligand has Y-type structurecontaining benzene ring, which favors spatial binding to the PPARδligand pocket. However, this ligand is a double-active ligand havingactivity to hPPARα as well, suggesting that selectivity to PPARδ isreduced. The PPARδ selective ligand GW501516([2-methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl]sulfanyl]phenoxy]aceticacid), recently developed by GlaxoSmithKline, exhibits much betterphysiological effect than any other ligands previously developed (Proc.Natl. Acad. Sci. USA 2001, 98, p 5306-5311).

The GW501516 has excellent affinity (1-10 nM) to PPARδ, and excellentselectivity to PPARα or PPARγ as well, which is at least 1000 times theselectivity of earlier ligands.

However, the PPARδ activity induced by all the ligands developed so faris only resulted from 30-40% of total ligand-binding pockets.

WO 2001-00603 applied by Glaxo group describes the compound representedby the following formula A containing the GW501516 as a selectiveactivator of PPARδ. However, this description includes only a part ofthe test results of GW501516 using Rhesus model.

[Wherein, R′ is CF₃ or F, R″ is H, CH₃ or Cl, and R′″ is H, CH₃ orCH₂CH₃.]

The thiazole compound represented by formula B as a PPARδ selectiveactivator has been described in WO 2002-62774 applied by Glaxo group.

WO 2003-072100 applied by Eli Lilly describes a pharmaceuticalcomposition for selective regulation of PPARδ containing the compoundrepresented by the following formula C.

However, the description only declares that the composition has beenprepared, which is produced as a racemate not as an optical isomercomprising two types. And the document only describes M⁺+1 value of massspectrometry of the produced racemate, which is confirmed by ¹H-NMR andacts as a selective activator of PPARδ, but does not mention about thepharmacological effect as a selective activator of PPARδ.

DISCLOSURE Technical Problem

The present inventors prepared an optical-active compound having highPPARδ selectivity among racemic compounds of the thiazole derivativedescribed in WO 2003-072100. Therefore, the object of the presentinvention is to provide the optical-active compound having high PPARδselectivity and a pharmaceutical composition, a functional cosmeticcomposition, and a composition for health food and animal feedscontaining the optical-active compound of the thiazole derivative.

Technical Solution

The present invention relates to the thiazole compound represented byformula 1 as a PPARδ (Peroxisome Proliferator Activated Receptor δ)ligand which can be used for the treatment of obesity, hyperlipidemia,arteriosclerosis, diabetes, dementia, Alzheimer's and Parkinson'sdisease and for strengthening muscles or improving memory, and apharmaceutical composition, a cosmetic composition, and a compositionfor health food and animal feeds containing the same.

WO 2003-072100 describes the thiazole compound represented by formula C.But, it only describes M⁺+1 value of mass spectrometry of the producedracemate, which is confirmed by ¹H-NMR and acts as a selective activatorof PPARδ; it does not describe the pharmacological effect as a selectiveactivator of PPARδ.

The above compound of formula C contains a chiral carbon and thus thereare stereoisomers thereof.

The present inventors confirmed that the R-form isomer represented byformula 1, the optical active isomer of the racemic compound of theformula C, has high selective activity to PPARδ but the S-form isomerrepresented by formula 2 shows significantly reduced activity to PPARδ.

So, the compound of formula 1 of the present invention is regarded as aselective invention of WO 2003-072100.

The compound represented by formula 1 of the present invention can beprepared by the following reaction formula 1.

[Wherein, R¹ is phenol protecting group, which can be C1-C4 lower alkyl,allyl, alkylsilyl, alkylarylsilyl or tetrahydropyranyl; R² is carboxylicacid protecting group containing C1-C4 alkyl or allyl; X¹ is bromineatom or iodine atom; X² and X³ are independently chlorine atom, bromineatom, iodine atom or leaving group having reactivity with nucleophilicsubstitution.]

Hereinafter, the preparation method of the invention is described indetail. However, the following descriptions cannot limit the scope northe spirit of the invention.

[Process A] Preparation of the Compound Represented by Formula 8

To prepare the compound represented by formula 8, 4-halo-2-methylphenol,the compound represented by formula 3 was treated with Grignard reagentto protect phenol group without an independent separation process, andreacted with an organic metal reagent and S stepwise, and finallyreacted with the compound represented by formula 7. This process has 4sub-reaction stages performed in a row.

The sub-reaction stages are described in detail hereinafter.

(Process A-1): The anhydride solvent used in this process is selectedfrom the group consisting of such single solvents as diethylether,tetrahydrofuran, hexane and heptane and mixed solvents comprising atleast two of these solvents. It is more preferred to selectdiethylether, tetrahydrofuran or the mixed solvent comprisingdiethylether and tetrahydrofuran as the anhydride solvent.

Grignard reagent used herein can be selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butylmagnesiumchloride (R₂MgCl) and alkylmagnesiumbromide (R₂MgBr).Among these, iso-propylmagnesiumchloride [(CH₃)₂CHMgCl] is mostpreferred.

The reaction temperature depends on a solvent, but it is generally setat −20˜40° C. and preferably at 0° C.˜room temperature (25° C.). Thereaction time depends on the reaction temperature and a solvent, but itis generally 10-60 minutes and preferably 10-30 minutes.

(Process A-2 and Process A-3): The organic metal reagent used forhalogen-lithium substitution can be selected from the group consistingof n-butyl lithium, sec-butyl lithium and tert-butyl lithium. Amongthese compounds, tert-butyl lithium is most preferred.

S with fine particles is preferred, which is added in a solventdirectly.

The reaction temperature depends on a solvent, but is generally set at−78˜25° C. The reaction temperature for halogen-metal substitution ispreferably −75° C. and the temperature for S introduction is −75˜roomtemperature (25° C.) The halogen-metal substitution reaction takes 10-30minutes and the S introduction reaction takes 30-90 minutes.

(Process A-4):5-halogenmethyl-4-methyl-2[4-(trifluoromethyl)phenyl]thiazole, thecompound represented by formula 7 used in this process was prepared bythe known method (WO 03/106442). Halogen of the compound represented byformula 7 is selected from the group consisting of chlorine, bromine andiodine. And among these, chlorine is most preferred.

The reaction temperature depends on a solvent, but it is generally setat −78˜25° C., more preferably at 0˜10° C. The reaction time isgenerally 10-120 minutes and preferably 10-60 minutes.

[Process B] Preparation of the Compound Represented by Formula 9

To prepare the compound represented by formula 9, the compoundrepresented by formula 8 is preferably reacted with the compoundgenerally used as phenol protecting group in the presence of base.

The aprotic polar solvent used in this process is selected from thegroup consisting of N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsilfoxide, acetonitrile, acetone, ethylacetate, carbontetrachloride, chloroform and dichloromethane. The ether herein can beselected from the group consisting of tetrahydrofuran, dioxane,dimethoxyethane, diethyleneglycoldimethylether andtriethyleneglycoldimethylether. The aromatic hydrocarbon is exemplifiedby benzene, toluene and xylene. As a solvent herein, the aprotic polarsolvent is preferred and particularly N,N-dimethylformamide, chloroformor dichloromethane is more preferred.

The base herein is amine including pyridine, triethylamine, imidazoleand N,N-dimethylaminopyridine. For the reaction of alkyl or allyletherified protecting group, such bases as sodium hydroxide, potassiumhydroxide, sodium carbonate and potassium carbonate are used. Inparticular, imidazole and potassium carbonate are more preferred.

Alkylsilylhalide or alkylarylsilylhalide is used as the silyl protectinggroup and 3,4-dihydro-2H-pyrane is used as the tetrahydropyranylprotecting group.

The reaction temperature depends on a solvent, but it is generally setat 10˜80° C., more preferably at 0˜room temperature (25° C.). Thereaction time depends on the reaction temperature and a solvent, butgenerally, it takes from one hour to one day. It is more preferred tofinish the reaction within 4 hours.

[Process C] Preparation of the Compound Represented by Formula 10

To prepare the compound represented by formula 10, α-proton of thioetherof the compound represented by formula 9 is treated with a strong alkalito give a nucleophile, which is reacted with various electrophiles.

The anhydride solvent used in this process is selected from the groupconsisting of such single solvents as diethylether, tetrahydrofuran,hexane and heptane and mixed solvents comprising at least two of thesesolvents. It is more preferred to select diethylether, tetrahydrofuranor the mixed solvent comprising diethylether and tetrahydrofuran as theanhydride solvent.

The strong alkali used for the a-proton extraction is selected from thegroup consisting of potassium tert-butoxide (t-BuOK), lithiumdiisopropyl amide (LDA), n-butyl lithium, sec-butyl lithium andtert-butyl lithium, and among these compounds, lithium diisopropyl amide(LDA) is most preferred.

The electrophile reacted with the nucleophile of thioether isbenzylhalide.

The reaction temperature depends on a solvent, but is generally −78˜25°C. It is more preferred to perform the α-proton extraction reaction inthe presence of a strong alkali at −75° C. at which electrophile isadded. Then, the temperature is raised slowly to room temperature (25°C.). The reaction time differs from each reaction stage. For example,the α-proton extraction by a strong alkali takes 10-30 minutes and thereaction with electrophile takes 30-90 minutes.

[Process D] Preparation of the Compound Represented by Formula 11

The compound represented by formula 11 is obtained by eliminating thephenol protecting group from the compound represented by formula 10.

The polar solvent used in this process is selected from the groupconsisting of N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsilfoxide, acetonitrile, acetone, ethylacetate, carbontetrachloride, chloroform and dichloromethane. The ether herein can beselected from the group consisting of tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycoldimethylether. The alcohol can bemethanol or ethanol. The aromatic hydrocarbon is exemplified by benzene,toluene and xylene. As a solvent herein, the polar solvent is preferredand particularly tetrahydrofuran is more preferred.

To eliminate the phenol protecting group, particularly to eliminatemethyl, ethyl, tert-butyl, benzyl or allylether protecting group,trimethylsilyliodide, ethanethioalcoholsodium salt, lithiumiodide,aluminum halide, boron halide or Lewis acid such as trifluoroacetic acidis used, and to eliminate the silyl protecting group such astrimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl andtert-butyldimethylsilyl, fluoride such as tetrabutylammoniumfluorine(Bu₄N⁺F⁻), halogen acid (hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydroiodic acid) or potassium fluoride is used. Itis preferred to use fluoride to eliminate the silyl protecting group andis more preferred to use tetrabutylammoniumfluorine.

The reaction temperature depends on a method and a solvent but isgenerally 0˜120° C. and preferably 10˜25° C. The reaction time dependson the reaction temperature, but generally it takes from 30 minutes toone day. It is more preferred to finish the reaction within 2 hours.

[Process E] Preparation of the Compound Represented by Formula 12

The compound is prepared by separating the R-isomer represented byformula 12 and another isomer S-isomer from the racemic compound offormula 11. This separation is performed by HPLC using a chiral normalphase column. At this time, the solvent is the mixed solvent comprisingnon-polar solvents such as hexane, heptane and pentane and polarsolvents such as ethanol and isopropyl alcohol.

[Process F] Preparation of the Compound Represented by Formula 13

To prepare the compound represented by formula 13, the compoundrepresented by formula 12 is preferably reacted with halogenacetatealkylester or halogenacetate allylester in the presence of base.

The halogenacetate alkylester or halogenacetate allylester is thegeneral compound that can be easily obtained. The halogen herein isexemplified by chlorine atom, bromine atom and iodine atom. Preferably,bromoacetate methylester, bromoacetate allylester or bromoacetateethylester is used as the halogenacetate alkylester or halogenacetateallylester.

The solvent used in this process can be a soluble single solventselected from the group consisting of N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethanoland methanol or a mixed solvent prepared by mixing these solvents with1-10% water. The most preferred solvent is the mixed solvent prepared bymixing acetone or dimethylsulfoxide with 1-5% water.

The base used in this process is not limited as long as it does not havea bad influence on the reaction, regardless of strong or weak, which isexemplified by alkali metal hydride such as sodium hydride and lithiumhydride, alkali earth metal hydride such as potassium hydride, alkalimetal hydroxide such as sodium hydroxide and potassium hydroxide, andalkali metal carbonate such as lithium carbonate, potassium carbonate,potassium bicarbonate and cesium carbonate. Among these compounds,alkali metal carbonate is preferred, and potassium carbonate is morepreferred.

The reaction temperature is not limited, but only up to the boilingpoint of a solvent. However, high temperature is not preferred toinhibit side reactions. The preferable reaction temperature is 0˜60° C.The reaction time differs from the reaction temperature, but isgenerally 30 minutes-1 day and preferably 30-90 minutes.

[Process G] Preparation of the Compound Represented by Formula 1

The compound represented by formula 1 is prepared from the compoundrepresented by formula 13 by hydrolyzing carboxylic acid ester of thecompound in the mixed solution of soluble inorganic salt and alcohol orsalts are prepared from allyl ester in the presence of a palladiumcatalyst.

The solvent used in this process is a soluble solvent that can be mixedwith water, for example alcohol such as methanol and ethanol. Theinorganic salt used in this process is an aqueous solution prepared bymixing alkali metal hydroxide such as lithium hydroxide, sodiumhydroxide and potassium hydroxide with water at the concentration of0.1-3 N, considering the type of carboxylic acid alkali salt. The acidused to obtain the compound represented by formula 13 as a carboxylicacid form is preferably acetic acid aqueous solution or 0.1-3 Nhydrochloric acid aqueous solution.

The reaction is preferably performed at a low temperature in order toinhibit side reactions, which is generally 0° C.-room temperature. Thereaction time depends on the reaction temperature, but is generally 10minutes-3 hours and more preferably 30 minutes-1 hour.

The pharmaceutically acceptable salt of the compound represented byformula 1 is prepared by allyl ester salt substitution from the compoundrepresented by formula 13 using palladiumtetrakistriphenylphosphinecatalyst and metal salt according to the reaction formula 2. The solventused in this process is selected from the group consisting ofchloroform, carbon tetrachloride, dichloromethane, tetrahydrofuran andethylacetate. The catalyst used in this process ispaladiumtetrakistriphenylphosphine. The salt for the salt substitutionis potassium 2-ethylhexanoate or sodium 2-ethylhexanoate.

The resultant compound containing S represented by formula 1 is a veryimportant material as a PPARδ protein ligand.

The present invention includes the compound represented by formula 1,solvates and salts thereof, which can be effectively used as aPeroxisome Proliferator Activated Receptor δ (PPARδ) activatorcomposition. Precisely, the compound represented by formula 1 of thepresent invention and pharmaceutically acceptable salts thereof can bevery effective as a pharmaceutical composition for the treatment andprevention of arteriosclerosis or hyperlipidemia; for increasing highdensity lipoprotein (HDL); for the treatment and prevention of diabetes;for the treatment and prevention of obesity; for strengthening muscle orenhancing endurance; for improving memory; for the treatment andprevention of dementia or Parkinson's disease; and a composition forhealth food supplements, health beverages, food additives and animalfeeds. The compound represented by formula 1 or pharmaceuticallyacceptable salts thereof of the present invention can be used for thefunctional cosmetic composition for prevention and improvement ofobesity and for the functional cosmetic composition for strengtheningmuscle and enhancing endurance. The functional cosmetic composition forstrengthening muscle and enhancing endurance can be formulated asointment, lotion, cream or gel to be applied on the body partbefore/after exercise and can be used for a long term to bring thewanted effect. The compound represented by formula 1 or pharmaceuticallyacceptable salts thereof of the present invention can be formulated asointment and be applied on the body part to prevent or treat diabetes ordiabetic foot ulcer, so-called diabetic ulcer.

The present invention also provides a peroxisome proliferator activatedreceptor δ (PPARδ) activator composition containing the thiazolecompound represented by formula 1 or pharmaceutically acceptable saltsthereof as an active ingredient.

The pharmaceutically acceptable salt herein includes all the salts thatare able to form salt with carboxylic acid of the compound of formula 1and alkali metal ions or alkali earth metal ions, which are exemplifiedby Li⁺, Na⁺, K⁺, Ca²⁺, etc.

The effective dose of the compound represented by formula 1 orpharmaceutically acceptable salts thereof of the present invention canbe determined according to the type of compound, administration method,target subject and target disease, but is determined based on theconventional medicinal standard. The preferable dose of the compoundrepresented by formula 1 is 1-100 mg/kg (body weight)/day. Theadministration frequency can be once or several times a day within theallowed one day dosage. The composition of the present invention can beadministered orally or parenterally and be used in general forms ofpharmaceutical formulation. For example, the composition of the presentinvention can be formulated as tablets, powders, dried syrups, chewabletablets, granules, capsules, soft capsules, pills, drinks, sublinguals,etc. The tablets of the present invention can be administered to asubject by a method or pathway that delivers the effective dose of thetablet with bioavailability, which is the oral. pathway. And theadministration method or the pathway can be determined according to thecharacteristics, stages of the target disease and other conditions. Whenthe composition of the present invention is formed as tablets, it canadditionally include one or more pharmaceutically acceptable excipients.The content and characteristics of the excipient can be determined bythe solubility and chemical properties of the selected tablet,administration pathway and standard pharmaceutical practice.

The compound of formula 1 of the present invention can be added tohealth food supplements or health beverages for the prevention andimprovement of hyperlipidemia; for increasing high density lipoprotein(HDL); for the prevention and improvement of diabetes; for theprevention and improvement of obesity; for strengthening muscle or forenhancing endurance; for improving memory; for the prevention andimprovement of dementia or Parkinson's disease. At this time, thecontent of the compound in those health food and beverages can beadjusted according to the purpose and application. In addition to theingredients mentioned above, the compound represented by formula 1 ofthe present invention can include in variety of nutrients, vitamins,minerals (electrolytes), flavors including natural flavors and syntheticflavors, coloring agents and extenders (cheese, chocolate, etc.), pecticacid and its salts, alginic acid and its salts, organic acid, protectivecolloidal viscosifiers, pH regulators, stabilizers, antiseptics,glycerin, alcohols, carbonators which are used to be added to soda, etc.

BEST MODE

Practical and presently preferred embodiments of the present inventionare illustrated as shown in the following Examples.

However, it will be appreciated that those skilled in the art, onconsideration of this disclosure, may make modifications andimprovements within the spirit and scope of the present invention.

Example 1 Preparation of the Compound of Formula 8 (Process A)

500 mg (2.14 mmol) of 4-iodo-2-methylphenol was dissolved in 20 ml ofanhydride tetrahydrofuran in the presence of nitrogen and, at that time,temperature was maintained at 0° C. 1.1 ml of isopropylmagnesiumchloride(2 M-ether solution, 2.16 mmol) was slowly added thereto, followed byreaction for 10 minutes. The reaction solution was cooled down to −78°C., to which 2.77 ml of tert-butyl lithium (1.7 M-heptane solution, 4.70mmol) was slowly added. After reacting for 20 minutes, 69 mg of S (2.14mmol) was slowly added thereto, followed by further reaction until thetemperature of the reactant reached 15° C. 40 minutes later, 624 mg(2.14 mmol) of5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazolerepresented by formula 7 was dissolved in 2 ml of anhydride THF, whichwas slowly added thereto at the same temperature. After one more hour ofreaction, the reaction was terminated by adding 20 ml of ammoniumchloride solution. The organic layer was separated and dried overmagnesium sulfate. After filtering, the solvent was distillated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1, v/v) to give 728 mg (yield:86%) of the target compound.

¹H NMR(300 MHz, CDCl₃) δ 7.96 (d, 2H, J=8.1 Hz), 7.65(d, 2H, J=8.3 Hz),7.19 (d, 1H, J=1.5 Hz), 7.01 (dd, 1H, J=8.2, 2.0 Hz), 6.62 (d, 1H, J=8.2Hz), 5.86 (brs, 1H), 4.07 (s, 2H), 2.19 (s, 3H), 2.12(s, 3H)

¹³C NMR(75.5 MHz, CDCl₃) δ 163.9, 155.5, 151.7, 137.4, 136.9, 133.5.131.9 (q, J=32.6 Hz), 131.7, 126.8, 126.3, (q, J=3.9 Hz), 125.8, 123.8,115.7, 33.2, 16.2, 14.8

Example 2 Preparation of the Compound of Formula 9 (R¹=t-Bu(CH₃)₂Si—,Process B)

500 mg (1.26 mmol) of the compound of formula 8 and 171 mg (2.52 mmol)of imidazole were completely dissolved in 5 ml of dimethylformamide. 209mg (1.38 mmol) of tert-butyldimethylsilylchloride was slowly addedthereto, followed by stirring at room temperature for 4 hours. Uponcompletion of the reaction, the organic solvent was extracted by usingammonium chloride solution and ethyl acetate. Moisture of the organiclayer was dried over magnesium sulfate. After filtering, the solvent wasdistillated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=10/1, v/v) togive 610 mg (yield: 95%) of the target compound.

¹H NMR (300 MHz, CDC1₃): 7.97 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=8.2 Hz),7.19 (d, 1H, J=1.9 Hz) 7.07 (m, 1H), 6.69 (d, 1H, J=8.3 Hz), 4.11 (s,2H), 2.21 (s, 3H), 2.11 (S, 3H), 1.01 (S, 9H), 0.21 (s, 6H) ¹³C NMR(75.5 MHz, CDCl₃): δ 163.2, 154.7, 151.5, 137.1, 136.6, 133.3, 132.4,131.7, 131.2, 131.0, 130.2, 129.2, 126.6, 126.1, 126.06, 126.01, 125.9,124.9, 119.4, 32.8, 25.9, 18.5, 16.9, 15.0, −4.0

Example 3 Preparation of the Compound of Formula 10 (R¹=t-Bu(CH₃)₂Si—,Process C)

300 mg (0.59 mmol) of the compound (R¹=t-Bu(CH₃)₂—) of formula 9prepared in Example 2 was dissolved in 5 ml of anhydride tetrahydrofuranin the presence of nitrogen and the temperature was lowered to −78° C.619 μl (2.0 M ether solution, 1.24 mmol) of lithium diisopropyl amidesolution was slowly added thereto, followed by reaction for 10 minutes.Then, 77 μl (0.65 mmol) of benzylbromide was added to the reactionsolution, followed by stirring for 30 minutes at the same temperature(−78° C.). The reaction was terminated by adding 5 ml of ammoniumchloride solution. Moisture of the organic layer was dried overmagnesium sulfate. After filtering, the solvent was distillated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=10/1, v/v) to give 265 mg (yield:75%) of the target compound.

¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, 2H, J=8.1 Hz), 7.65 (d, 2H,J=8.2Hz), 7.03-7.26 (m, 7H) 6.63 (d, 1H, J=8.3 Hz), 4.51 (dd, 1H, J=9.8,5.3 Hz), 3.37 (dd, 1H, J=9.8, 5.3 Hz), 3.05 (dd, 1H, J=13.6, 9.9 Hz),2.10 (s, 3H), 1.83 (s, 3H), 0.98 (s, 9H) , 0.18 (s, 6H) 13C NMR (75 MHz,CDCl3): δ 163.5, 155.1, 151.8, 138.4, 137.7, 136.5, 133.5, 130.3, 129.3,128.9, 127.2, 126.8, 126.7, 126.2, 126.1, 124.5, 119.4, 49.2, 44.4,26.1, 18.7, 17.1, 15.1, −3.81, −3.84

Example 4 Preparation of the Compound of Formula 11 (Process D)

200 mg (0.33 mmol) of the compound (R¹=t-Bu(CH₃)₂Si—) of formula 10prepared in Example 3 was dissolved in 5 ml of anhydride tetrahydrofuranin the presence of nitrogen. 660 μl (0.66 mmol) oftetrabutylammoniumfluoride 1 M tetrahydrofuran solution was slowly addedthereto at room temperature, followed by stirring for 1 hour. Uponcompletion of the reaction, the organic layer was separated by addingethyl acetate and water. Moisture of the organic layer was dried overmagnesium sulfate. After filtering, the solvent was distillated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=5/1, v/v) to give 146 mg (yield:91%) of the target compound.

¹H NMR (500 MHz, CDCl₃): δ 7.92 (d, 2H, J=8.2 Hz), 7.50 (s, 1H), 7.59(d, 2H, J=8.2Hz), 7.07-7.22 (m, 6H), 6.85(m, 1H), 6.44 (d, 1H, J=8.2Hz), 4.47 (dd, 1H, J=9.7, 5.4 Hz), 3.39 (dd, 1H, J=13.8, 5.4 Hz), 3.06(dd, 1H, J=13.8, 9.8 Hz), 2.12 (s, 3H), 1.73 (s, 3H) ¹³C NMR (125 MHz,CDCl3): δ 164.1, 155.7, 151.2, 138.0, 137.9, 137.0, 136.4, 133.8, 131.8,131.5, 129.0, 128.6, 127.2, 127.0, 126.6, 126.14, 126.11, 125.7, 125.0,122.9, 122.7, 115.2, 60.8, 49.1, 43.7, 21.2, 15.9, 14.3, 14.2

Example 5 Preparation of the Compound of Formula 12 (Process E)

90 mg of the compound of formula 11 prepared in Example 4 proceeded tosemiprep chiral HPLC column (chiralpack AD-H) to give 45 mg of thetarget compound represented by formula 12 in R-form and 45 mg of itscorresponding isomer in S-form.

Moving phase: hexane/isopropyl alcohol: 90/10

Flow rate: 3 ml/min

Example 6 Preparation of the Compound of Formula 13 (Process F)

20 mg (0.04 mmol) of the compound of formula 12 prepared in Example 5was well mixed with 10 ml of acetone containing 5% water and 127 mg (0.9mmol, 2.3 equivalent) of potassium carbonate at room temperature. 67 μl(0.6 mmol, 1.5 equivalent) of bromoacetateethylester was added thereto,followed by vigorous stirring for 4 hours. Upon completion of thereaction, the organic solvent was extracted by using sodium chloridesolution and ethylacetate, which was dried over magnesium sulfate toeliminate moisture of the organic layer. After filtering, the solventwas distillated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=5/1, v/v) to give22 mg (yield: 95%) of the target compound of formula 13.

¹H NMR (300 MHz, CDCl3): 7.98 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=8.3 Hz),7.06-7.27 (m, 7H), 6.55 (d, 1H, J=8.4 Hz), 4.59 (s, 2H), 4.53 (dd, 1H,J=9.7, 5.3 Hz), 4.22 (q, 2H, J=7.1 Hz), 3.37 (dd, 1H, J=13.7, 5.3 Hz),3.17 (m, 1H) 2.20 (s, 3H), 1.83 (s, 3H), 1.26 (t, 3H, J=7.2 Hz) ¹³C NMR(75 MHz, CDCl₃): 169.1, 163.6, 156.9, 151.8, 138.3, 137.4, 137.3, 136.4,133.4, 129.3, 128.9, 128.6, 127.2, 126.8, 126.3, 126.2, 126.1, 125.1,111.8, 65.9, 61.7, 49.1, 44.4, 16.5, 15.1, 14.5

Example 7 Preparation of the Compound of Formula 1 (Process G)

20 mg (0.03 mmol) of the compound of formula 13 prepared in Example 6was mixed well with 15 ml of ethanol, to which 15 μl of 3 N sodiumhydroxide solution was added. After stirring at room temperature for 20minutes, pH of the reaction mixture was adjusted to 2.0 by 2 N HCl.Vacuum distillation was performed to eliminate ethanol about 80%. Theorganic solvent was extracted by using sodium chloride solution andethyl acetate. After filtering, the solvent was distillated underreduced pressure, and the residue was purified by LH-20 columnchromatography to give 16 mg (yield: 98%) of the target compound offormula 1.

¹H NMR (500 MHz, CDC13): δ 7.92 (d, 2H, J=8.2 Hz), 7.50 (s, 1H), 7.59(d, 2H, J=8.2Hz), 7.07-7.22 (m, 6H), 6.85 (m, 1H), 6.44 (d, 1H, J=8.2Hz), 4.47 (dd, 1H, J=9.7, 5.4 Hz), 3.39 (dd, 1H, J=13.8, 5.4 Hz), 3.06(dd, 1H, J=13.8, 9.8 Hz), 2.12 (s, 3H), 1.73 (s, 3H) ¹³C NMR (125 MHz,CDCl₃): δ 164.1, 155.7, 151.2, 138.0, 137.9, 137.0, 136.4, 133.8, 131.8,131.5, 129.0, 128.6, 127.2, 127.0, 126.6, 126.14, 126.11, 125.7, 125.0,122.9, 122.7, 115.2, 60.8, 49.1, 43.7, 21.2, 15.9, 14.3, 14.2

Experimental Example 1 Activity and Cytotoxicity Test

The PPARδ activities of the R-form compound represented by formula 1 ofthe present invention and the S-form compound represented by formula 2were measured by transfection assay. In addition, the selectivity toPPAR subtypes, PPARα and PPARγ, was examined. Cytotoxicity was tested byMTT assay and in vivo activity and toxicity was investigated by animalexperiment using mice.

[Transfection Assay]

CV-1 cells were used in this assay. The cells were inoculated in a96-well plate containing DMEM supplemented with 10% FBS, DBS(delipidated) and 1% penicillin/streptomycin and cultured in a 37° C.,5% CO₂ incubator. The experiment was performed according to the steps ofinoculation, transfection, sample treatment and confirmation.Particularly, CV-1 cells were inoculated in a 96 well-plate (5000cells/well), followed by transfection 24 hours later. Full length PPARsplasmid DNA, reporter DNA confirming PPARs activity owing to itsluciferase activity, β-galactosidase DNA providing information ontransfection efficiency, and transfection reagent were used for thetransfection. The compounds of formula 1 and formula 2 were dissolved indimethylsulfoxide (DMSO), which were treated to the cells via media atdifferent concentrations. After culturing the cells in the incubator for24 hours, the cells were lysed by using lysis buffer. Luciferaseactivity and β-galactosidase activity were measured with Luminometer anda microplate reader. The obtained values of luciferase were modified bythe values of β-galactosidase. A graph was made with those values andEC₅₀ was calculated.

TABLE 1 EC₅₀ (nM) compound PPARδ PPARα PPARγ

formula 1 0.6 ia ia

formula 2 5.1 ia ia

As shown in Table 1, the compound represented by formula 1 of thepresent invention is highly selective to PPARδ. The thiazole compound offormula 1 of the present invention demonstrated 100,000 times higherselectivity to PPARα and PPARγ. EC₅₀ of the compound of formula 1 toPPARδ was 0.6 nM and EC₅₀ of the compound of formula 2 to PPARδ was 5.1nM. R-isomer, the compound of formula 1 of the present invention,exhibited 10 times stronger activity than S-isomer, the compound offormula 2. The above results indicate that the compound of formula 1 ofthe present invention has high selectivity.

[MTT Assay]

MTT assay was performed to test cytotoxicity of the compounds of thepresent invention. MTT is a yellow substance soluble in water, but whenit is introduced into a living cell, it turns into a purple insolublecrystal by dehydrogenase in mitochondria. Cytotoxicity can be confirmedby measuring OD₅₅₀ after dissolving MTT in dimethylsulfoxide. Theexperiment was performed as follows.

CV-1 cells were inoculated in a 96-well plate (5000 cells/well). Thecells were cultured in a 37° C. 5% CO₂ incubator for 24 hours, andtreated with the compounds of formula 1 and formula 2 at differentconcentrations. Then, the cells were cultured for 24 hours again, towhich MTT reagent was added. After culturing for 15 minutes, thegenerated purple crystals were dissolved in dimethylsulfoxide. Opticaldensity was measured with a microplate reader to confirm cytotoxicity.As a result, the compound represented by formula 1 of the presentinvention and the compound represented by formula 2, the optical isomerthereof, were confirmed not to have cytotoxicity even at theconcentration of 100,000 times the EC₅₀ value.

[Toxicity Test]

Acute toxicity and reproductive toxicity tests were performed using miceto evaluate the toxicity of the compound of the present invention. Thecompound of formula 1 was orally administered to ICR mice at 6 weeks atthe dosage of 50 mg/kg, 300 mg/kg and 2000 mg/kg, followed byobservation on toxicity for 14 days. As a result, no death was observedaccording to the administration of the compound of formula 1 even withthe highest concentration of 2000 mg/kg, and no significant changes onweight and feed taking were observed either. Autopsy results showed noabnormal signs. The result of reproductive toxicity test using C57BL/6mice was also consistent with the above, which is no toxicity caused bythe compound of formula 1 was observed. After oral-administration of thecompound to the pregnant female mice, weight gain and growth speed offetus were investigated. As a result, no significant differenceaccording to the administration was observed and no changes in bonedevelopment and disease related matters were observed.

[Animal Test] [Obesity Inhibitory Effect]

An animal test using mice was performed to confirm the in vivo effect ofthe compound of the present invention. C57BL/6 (SLC Co.) mice at 14weeks were used. To induce obesity, feeds containing 35% fat were given.While feeding such high-fat feeds for 35 days, vehicle, GW501516 (10mg/Kg/day) and the compound of formula 1 of the present invention (10mg/Kg/day) were orally administered. As a result, only 26.5% of thegroup treated with GW501516, 23.1% of the group treated with thecompound of the present invention showed weight increase, compared withthe vehicle treated group (58.9%), which was approximately ½ increasecompared with the vehicle treated group. Therefore, the compound offormula 1 of the present invention was confirmed to have strong obesityinhibiting effect, which was much more excellent than GW501516.

[Diabetes Improving Effect]

GTT (glucose tolerance test) was performed to confirm the diabetesimproving effect of the compound of the present invention. Glucose (1.5g/Kg) was intra-abdominally administered to the mice pre-treated orallywith samples for 78 days. Blood glucose was measured every hour. Fastingblood glucose was lower in the group treated with the compound of thepresent invention than in the group treated with vehicle or GW501516.The group treated with the compound of the present invention exhibitedrapid blood glucose decrease in 20-40 minutes and glucose clearance in100 minutes. In the meantime, the blood glucose level was not recoveredto normal in the vehicle treated group even after 120 minutes. TheGW501516 treated group showed lower blood glucose than the vehicletreated group but the blood glucose level was not recovered to normal.The above results indicate that the compound of formula 1 of the presentinvention had excellent diabetes improving effect.

[Hyperlipidemia Improving Effect]

In vivo animal test using C57BL/6 (SLC Co.) mice at 6 weeks wasperformed to confirm the hyperlipidemia improving effect of the compoundof the present invention. The animals were orally administered with 10mg/kg/day of the compound of formula 1 of the present invention andGW501516 while being fed with high fat feeds. 6 weeks later, blood wastaken from orbital veins. Serum was separated and blood HDL level wasmeasured by biochemical method. As a result, HDL level was 36.3%increased in the group treated with GW501516, compared with the control.HDL level was 44.6% increased in the group treated with the compound offormula 1 of the present invention. The above results indicate that thecompound of formula 1 of the present invention increases blood HDL moreeffectively than GW501516.

[Arteriosclerosis Inhibiting Effect]

In vivo animal test using ApoE−/− mouse, which is an animal model forarteriosclerosis, was performed to confirm the arteriosclerosisinhibiting effect of the compound of the present invention. The animalswere orally administered with 2 mg/kg/day of the compound of formula 1of the present invention while feeding with high fat, high cholesterolfeeds (20% fat, 1.25% cholesterol; AIN-93G diet). 28 days later, plaquestaining was performed over the whole artery using Sudan IV toinvestigate the arteriosclerosis inhibiting effect of the compound bycomparing the results between experimental and control groups. As aresult, arteriosclerosis was 30% inhibited in ApoE−/− mouse treated withthe compound of formula 1 of the present invention, compared with thecontrol.

[Muscle Endurance Strengthening and Muscle Function Enhancing Effect]

An animal test was performed to confirm muscle endurance strengtheningand muscle function enhancing effect of the compound of the presentinvention. Most muscles are generated in the developmental stage. Thus,the compound of formula 1 (10 mg/Kg/day) were orally administered topregnant mice in the period of either pregnancy or lactation or bothpregnancy and lactation. Weight gain and growth rate were not muchdifferent between fetuses of the control group and the treatment group.Muscles were observed after removing skin. As a result, muscles of thetreatment group were red, unlike the controlled one. ATPase staining andimmunostaining were performed. As a result, type I muscle fiber wasincreased in the group treated with the compound of formula 1. Theeffect of the changes of the muscle fiber on the enhancement of muscleendurance and muscle function was investigated by using treadmill test.As a result, running time was much extended in the group treated withthe compound of formula 1.

TABLE 2 Results of muscle endurance test Increasing rate (treatmentgroup/control group) Pregnancy + pregnancy lactation lactation timelength time length time length treatment 2.3 2.4 2.1 2.2 2.9 3.0 grouptimes times times times times times

When the compound of the present invention was treated to adults, muscleendurance and muscle function were also enhanced. Particularly, thecompound of formula 1 was orally administered to C57BL/6 mice at 10weeks at the concentration of 10 mg/kg, during which the mice wereforced to exercise. The exercise was performed with treadmill for 30minutes once a day for 30 days, precisely at the speed of 2 meter/minfor the first 5 minutes, at 5 meter/min for 5 minutes, at 8 meter/minfor 5 minutes and at 20 meter/min for the last 5 minutes. At the finish,muscle endurance and muscle function enhancing effect was tested byusing treadmill. As a result, the time (1.5 fold) and distance (1.6fold) of exercise were all increased in the group treated with thecompound of the present invention, when compared with the control.

[Memory Improvement]

An animal test was performed to investigate the therapeutic effect ofthe compound of the present invention on dementia and Parkinson'sdisease based on the memory improving effect thereof. To confirm theeffect of the compound of the present invention in the period of braindevelopment, the compound was orally administered to pregnant mice atthe concentration of 10 mg/kg in the periods of pregnancy and lactation.Morris water maze test was performed to detect any changes of the brainfunctions of the treatment group and the control group. As a result, theaverage time spent to find the platform was much shorter in the grouptreated with the compound of formula 1, compared with the control group;precisely, the treatment group spent 6.8 sec to find the platform andthe control group spent 24.2 sec at average, suggesting that thecompound of formula 1 had an excellent memory improving effect.

The therapeutic effect of the compound of the present invention ondementia and Parkinson's disease based on the memory improving effectthereof was investigated using brain disease animal model (C57BL/6 miceat 10 weeks). First, LPS was injected into the mouse brain to constructbrain disease animal model. The mice were divided into four groupsaccording to the administration and exercise. The exercise was performedwith treadmill at the speed of 2 meter/min for the first 5 minutes, at 5meter/min for 5 minutes, at 8 meter/min for 5 minutes and at 20meter/min for the last 5 minutes. At the finish, Morris water maze testwas performed. The results are summarized in Table 3. As a result, thetherapeutic effect of the compound of formula 1 of the present inventionon dementia and Parkinson's disease via memory enhancement by thecompound and exercise was confirmed in the brain disease animal model.

TABLE 3 Results of water maze test Experiment group Results of watermaze test control group Exercise (X) 36 seconds Exercise (◯) 29 secondstreatment group Exercise (X) 25 seconds Exercise (◯) 13 seconds

INDUSTRIAL APPLICABILITY

The thiazole derivative compound of the present invention as a PPARδligand, which has selective meanings from prior inventions, can beeffectively used as a pharmaceutical composition for the treatment andprevention of arteriosclerosis or hyperlipidemia; for increasing highdensity lipoprotein (HDL); for the treatment and prevention of diabetes;for the treatment and prevention of obesity; for strengthening muscle orenhancing endurance; for improving memory; for the treatment andprevention of dementia or Parkinson's disease; and a composition forhealth food supplements, health beverages, food additives, functionalcosmetics and animal feeds.

1. A thiazole compound represented by formula 1 or pharmaceuticallyacceptable salts thereof.


2. A pharmaceutical composition for the prevention and treatment ofarteriosclerosis or hyperlipidemia containing the thiazole compoundrepresented by formula 1 or pharmaceutically acceptable salts thereof ofclaim 1 as an active ingredient.
 3. A pharmaceutical composition forincreasing the level of high density lipoprotein (HDL) containing thethiazole compound represented by formula 1 or pharmaceuticallyacceptable salts thereof of claim 1 as an active ingredient.
 4. Apharmaceutical composition for the prevention and treatment of diabetescontaining the thiazole compound represented by formula 1 orpharmaceutically acceptable salts thereof of claim 1 as an activeingredient.
 5. A pharmaceutical composition for the prevention andtreatment of obesity containing the thiazole compound represented byformula 1 or pharmaceutically acceptable salts thereof of claim 1 as anactive ingredient.
 6. A pharmaceutical composition for strengtheningmuscle or for enhancing endurance containing the thiazole compoundrepresented by formula 1 or pharmaceutically acceptable salts thereof ofclaim 1 as an active ingredient.
 7. A pharmaceutical composition forimproving memory or for the prevention and treatment of dementia orAlzheimer's or Parkinson's disease containing the thiazole compoundrepresented by formula 1 or pharmaceutically acceptable salts thereof ofclaim 1 as an active ingredient.
 8. A health food adjuvant or healthbeverage containing the thiazole compound represented by formula 1 orpharmaceutically acceptable salts thereof of claim 1 as an activeingredient.
 9. The health food adjuvant or health beverage according toclaim 9, wherein the health food adjuvant or health beverage is used forthe prevention and improvement of arteriosclerosis or hyperlipidemia;for increasing high density lipoprotein (HDL); for the prevention andimprovement of diabetes; for the prevention and improvement of obesity;for strengthening muscle or enhancing endurance; for improving memory;and for the prevention and improvement of dementia or Alzheimer's orParkinson's disease.
 10. A food additive containing the thiazolecompound represented by formula 1 or pharmaceutically acceptable saltsthereof of claim 1 as an active ingredient.
 11. The food additiveaccording to claim 10, wherein the food additive is used for theprevention and improvement of arteriosclerosis or hyperlipidemia; forincreasing high density lipoprotein (HDL); for the prevention andimprovement of diabetes; for the prevention and improvement of obesity;for strengthening muscle or enhancing endurance; for improving memory;and for the prevention and improvement of dementia or Alzheimer's orParkinson's disease.
 12. An animal feed composition containing thethiazole compound represented by formula 1 or pharmaceuticallyacceptable salts thereof of claim 1 as an active ingredient.
 13. Theanimal feed composition according to claim 12, wherein the animal feedcomposition is used for the prevention and improvement ofarteriosclerosis or hyperlipidemia; for increasing high densitylipoprotein (HDL); for the prevention and improvement of diabetes; forthe prevention and improvement of obesity; for strengthening muscle orenhancing endurance; for improving memory; and for the prevention andimprovement of dementia or Alzheimer's or Parkinson's disease.
 14. Afunctional cosmetic composition containing the thiazole compoundrepresented by formula 1 or pharmaceutically acceptable salts thereof ofclaim 1 as an active ingredient.
 15. The functional cosmetic compositionaccording to claim 14, wherein the functional cosmetic composition isused for the prevention and improvement of obesity; and forstrengthening muscle or enhancing endurance.
 16. A peroxisomeproliferator activated receptor δ (PPARδ) activator compositioncontaining the thiazole compound represented by formula 1 orpharmaceutically acceptable salts thereof of claim 1 as an activeingredient.